ABSTRACT Heart failure (HF) remains an enormous public health problem despite advances in treatment. Disease progression and response to therapy in HF varies widely between individuals, but breakthrough technologies such as genomics and metabolomics are helping to unravel the disease heterogeneity that confounds patient management. Perturbed energy metabolism may be a key contributor to cardiac dysfunction and the development of clinical HF. Evidence from a variety of sources indicates that impaired structure and function of the energetic apparatus in the myocardium contributes to disease severity, progression, and may influence response to treatment. However, in order to advance these observations toward meaningful interventions for HF patients, several key steps are still needed: 1) confirming the importance of metabolic variation in human HF, 2) developing noninvasive markers of myocardial energetic status, and 3) identifying promising targets for intervention. Our proposed project is a series of interwoven translational investigations in humans and dogs with HF to define the association of plasma metabolite levels with disease severity, myocardial energetics, and disease progression. This project leverages substantial infrastructure already in place a large existing genetic cohort study, available plasma samples suitable for metabolomic profiling, comprehensive translational laboratory capabilities, and a cohesive multidisciplinary research group focused on HF. Together the planned studies will address the overarching hypothesis that the peripheral metabolomic signature can indicate disease progression/treatment responsiveness in HF patients and that this is driven by altered myocardial energy metabolism. If true, then these data will help advance personalized therapy and identify novel targets for HF intervention, leading to improved outcomes for HF patients.